Protein‐Nanocaged Selenium Induces t(8;21) Leukemia Cell Differentiation via Epigenetic Regulation

Abstract The success of arsenic in degrading PML‐RARα oncoprotein illustrates the great anti‐leukemia value of inorganics. Inspired by this, the therapeutic effect of inorganic selenium on t(8; 21) leukemia is studied, which has shown promising anti‐cancer effects on solid tumors. A leukemia‐targeting selenium nanomedicine is rationally built with bioengineered protein nanocage and is demonstrated to be an effective epigenetic drug for inducing the differentiation of t(8;21) leukemia. The selenium drug significantly induces the differentiation of t(8;21) leukemia cells into more mature myeloid cells. Mechanistic analysis shows that the selenium is metabolized into bioactive forms in cells, which drives the degradation of the AML1‐ETO oncoprotein by inhibiting histone deacetylases activity, resulting in the regulation of AML1‐ETO target genes. The regulation results in a significant increase in the expression levels of myeloid differentiation transcription factors PU.1 and C/EBPα, and a significant decrease in the expression level of C‐KIT protein, a member of the type III receptor tyrosine kinase family. This study demonstrates that this protein‐nanocaged selenium is a potential therapeutic drug against t(8;21) leukemia through epigenetic regulation.


Figure S1 .
Figure S1.TEM images of (A) the ferritin shell and (B) the selenium core of HFn-Se.Scale bar = 100 nm.C. Binding capacity of HFn on different solid tumor cells.

Figure S4 .
Figure S4.The binding and cytotoxic effect of V9-HFn to normal cells.A. The targeted binding analysis of V9-HFn to HUVECs cells.Light chain ferritin (LFn) was chosen as a negative control.B. Cell viability analysis of HUVECs cells treated with V9-HFn (n = 3).The data represents mean ± SD.

Figure S6 .
Figure S6.Immunoblotting was performed to assess the protein expression levels of TfR1 (A) and ITGA4 (C) in various leukemia cells.Quantification of the immunoblot signals was conducted to determine the relative abundance of TfR1 (B) and ITGA4 (D) proteins in the different cell lines (n = 3).Protein intensity of TfR1 and ITGA4 were quantified and represented as relative protein levels normalized to β-actin.E. Cell viability analysis of Kasumi-1 and U937 cells treated with V9-HFn-Se (n = 3).The data represent mean ± SD.

Figure S11 .
Figure S11.Effects of V9-HFn-Se on the cell cycle of Kasumi-1 cells.

Figure S14 .
Figure S14.The qPCR analysis shows the level of AML1-ETO in Kasumi-1 cells treated with 90 μg/mL V9-HFn-Se for 48 hours (n = 3).ns: not significant.One-way ANOVA with Tukey's test was performed.The data represents mean ± SD.